Estimated glomerular filtration rate with and without race for drug dosing: Cystatin C vs. serum creatinine.

The goal of this study was to use a model kidney function clearance-dependent drug (vancomycin) to understand the gain or loss of precision in dosing with use of serum creatinine (Scr ), serum cystatin C (Scys ) and race and nonrace-based equations of the estimated glomerular filtration rate (eGFR). In this study of hospitalized patients, we compared Scr , Scys and their combination to estimate kidney function and vancomycin clearance. The nonrace-based Scys eGFR model outperformed other clearance models and improved the probability of target attainment by 15%. When Scys is not available, we show that the new 2021 CKD-EPI eGFRcr equation (no race factor) performs as well as the current conventional approach. This improvement in model performance does not negate the need for individualized dosing but exemplifies the need to remove race as a factor of kidney-function dose adjustment.

Comparison of Race-Based and Non-Race-Based Equations for Kidney Function Estimation in Critically Ill Thai Patients for Vancomycin Dosing.

Empiric antibiotic dosing frequently relies on an estimate of kidney function based on age, serum creatinine, sex, and race (on occasion). New non-race-based estimated glomerular filtration rate (eGFR) equations have been published, but their role in supporting dosing is not known. Here, we report on a population pharmacokinetic model of vancomycin that serves as a useful probe substrate of eGFR in critically ill Thai patients. Data were obtained from medical records during a 10-year period. A nonlinear mixed-effects modeling approach was conducted to estimate vancomycin parameters. Data from 208 critically ill patients (58.2% men and 36.0% septic shock) with 398 vancomycin concentrations were collected. Twenty-three covariates including 12 kidney function estimates were tested and ranked on the basis of the model performance. The median (min, max) age, weight, and serum creatinine was 69 (18, 97) years, 60.0 (27, 120) kg, and 1.53 (0.18, 7.15) mg/dL, respectively. The best base model was a 1-compartment linear elimination with zero-order input and proportional error model. A Thai-specific eGFR equation not indexed to body surface area model best predicted vancomycin clearance (CL). The typical value for volume of distribution and CL was 67.5 L and 1.22 L/h, respectively. A loading dose of 2000 mg followed by maintenance dose regimens based on eGFR is suggested. The Thai GFR not indexed to BSA model best predicts vancomycin CL and dosing in the critically ill Thai population. A 5% to 10% absolute gain in the vancomycin probability of target attainment is expected with the use of this population-specific eGFR equation.

Modeling Kinetic Glomerular Filtration Rate in Adults with Stable and Unstable Kidney Function: Vancomycin as the Motivating Example.

BACKGROUND: Equations used to estimate kidney function for drug dosing rely on the assumption of homeostasis to translate a single-point measurement of serum creatinine into clearance (CL). Our objective was to rank order the performance of alternate kidney function equations as predictors of drug CL in stable and unstable patients. METHODS: Data were extracted from medical records at a single center for all adult patients treated with vancomycin over a 5-year period for population pharmacokinetic analysis. This analysis focused on comparison of nine kidney function equations as covariates of vancomycin CL. Both body surface area (BSA) indexed (ml/min/1.73 m2 ) and unindexed units (ml/min) of kidney function were tested, as time-varying and time-invariant covariates of vancomycin CL. RESULTS: The final data set consisted of 2640 patients (62% male, 81% white) with 6628 concentration measurements. The median (5th, 95th percentile) of measurements per patient, age, weight, body mass index (BMI) was 2 (1, 7) concentrations, 61.5 (28, 83) years, 90.0 (56.7, 147) kg, and 30.0 (20.7, 48.0) kg/m2 . Unstable kidney function was documented in 43.6% of patients, primarily as acute kidney injury (AKI) on admission with improvement (19.4%) and AKI during the admission (17.4%). Models based on time-varying kidney function estimates performed better than as time-invariant. Kidney function estimated by the Chen method was ranked higher than other estimation methods. CONCLUSIONS: A time-varying kinetic estimated glomerular filtration rate method not indexed to BSA was identified as the highest ranked covariate model of vancomycin CL.

Comparison of Body Size, Morphomics, and Kidney Function as Covariates of High-Dose Methotrexate Clearance in Obese Adults with Primary Central Nervous System Lymphoma.

BACKGROUND: High-dose methotrexate (HD-MTX) is used to treat primary central nervous system lymphoma (PCNSL), but potential differences in MTX clearance (CL) due to obesity have not been studied. We characterized the relationship between HD-MTX CL and computed tomography (CT)-generated body composition (morphomic), body size descriptors, and laboratory measurements in a cohort of obese and non-obese patients with PCNSL. METHODS: Medical records from adult patients with PCNSL treated with HD-MTX over a 10-year period were queried. Individuals with CT data within 30 days of the first cycle of treatment were included. Population pharmacokinetic analysis was performed using a 2-compartment base structural model. We specifically compared body surface area (BSA) to standard body size, morphomic, and renal function estimation methods as covariates of HD-MTX CL. RESULTS: The final data set consisted of non-obese (n=45) and obese (n=28) patients with 291 observations (3-7 samples per patient) with a mean (standard deviation) weight of 69.8 (11.6) kg and 104 (14.9) kg, respectively (p=0.0001). Vertebral body height was more informative than BSA of MTX CL. Similarly, a CL model incorporating age, albumin, and serum creatinine was more informative than kidney function equations and body size. The final model of MTX CL was based on age, albumin, serum creatinine, and vertebral body height. CONCLUSIONS: Common clinical variables coupled with vertebral body height are more predictive of first cycle MTX CL than BSA, alternate body size descriptors, and commonly used kidney function equations.

Quaternary-centre-guided synthesis of complex polycyclic terpenes.

The presence of a quaternary centre-a carbon with four other carbons bonded to it-in any given molecule can have a substantial chemical and biological impact. In many cases, it can enable otherwise challenging chemistry. For example, quaternary centres induce large rate enhancements in cyclization reactions-known as the Thorpe-Ingold effect-which has application in drug delivery for molecules with modest bioavailability1. Similarly, the addition of quaternary centres to a drug candidate can enhance both its activity and its metabolic stability2. When present in chiral ligands3, catalysts4 and auxiliaries5, quaternary centres can guide reactions toward both improved and unique regio-, stereo- and/or enantioselectivity. However, owing to their distinct steric congestion and conformational restriction, the formation of quaternary centres can be achieved reliably by only a few chemical transformations6,7. For particularly challenging cases-for example, the vicinal all-carbon8, oxa- and aza-quaternary centres9 in molecules such as azadirachtin10,11, scopadulcic acid A12,13 and acutumine14-the development of target-specific approaches as well as multiple functional-group and redox manipulations is often necessary. It is therefore desirable to establish alternative ways in which quaternary centres can positively affect and guide synthetic planning. Here we show that if a synthesis is designed such that each quaternary centre is deliberately leveraged to simplify the construction of the next-either through rate acceleration or blocking effects-then highly efficient, scalable and modular syntheses can result. This approach is illustrated using the conidiogenone family of terpenes as a representative case; however, this framework provides a distinct planning logic that is applicable to other targets of similar synthetic complexity that contain multiple quaternary centres.